Background/Purpose: The clinical phenotype of rheumatoid arthritis (RA) ranges from mild joint inflammation to severe joint destruction, but molecular factors responsible for variability are incompletely understood, particularly in African-Americans. We tested the hypotheses that expression of immune-related genes in PBMCs differ in:  a) severe vs mild radiographic damage;  b) early or longstanding disease;  c) RA vs control. 

Methods: We analyzed total RNA from the PBMC of 60 African Americans from the CLEAR Registry (of a total of ~1,060 RA patients and 550 controls). Extremes of phenotype were analyzed:  10 RA with early disease/low damage (EL); 10 RA with early disease/high damage (EH); 10 RA with late disease/low damage (LL); late disease/high damage (LH) and 20 age, race and gender matched healthy controls. Early disease was defined as disease duration < 2 years. Late disease ranged from 9.5 to >60 years duration (Table 1). Radiographic severity was defined as total Sharp/van der Heijde scores of hands/feet. All participants had ACPA positive RA. We performed TaqMan qRT-PCR for 165 independent genes using panels based on specific pathways:  SAB Innate and Adaptive Immune Signaling, and AB Immune Panel. The normalized gene expression levels (dCt) were compared between each RA group and the controls using a two-group t test.

Results: Preliminary results (Table 2) indicate a statistically significant increase (compared to controls) in gene expression in the EH category for the following genes: TLR2, TLR4, TLR8, INFGR1, INFGR2, MAPK14.  In addition, EH subjects had lower expression of MIF and IKBKB. High expression of TLR8 was associated with the LH group, while low expression of TOLLIPwas associated with both the EL and LL groups. The expression of these genes is rarely increased in mild disease, especially in the LL goup. These preliminary results suggest that high expression of genes in the Toll-like receptor and interferon pathways are associated with radiographic damage in African-Americans with RA. 

Conclusion: These results will inform further studies of predictors of RA severity in African Americans using ~300 subjects from the CLEAR Registry, and have important implications regarding pathogenesis of radiographic damage of RA. 

Table 1. Clinical and demographic characteristics.

 

Variable	Control Group	EH Group	EL Group	LH Group	LL Group
Age (years)	35-69	23-75	34-62	35-76	47-68
Disease duration (months)	NA	2-23	0-5	114-522	189-339
Anti-CCP antibody  status (ACPA)	Negative	Positive	Positive	Positive	Positive
Total Sharp/ van der Heijde score	NA	11-53	0	181-341	0

Table 2. Gene expression difference between RA groups and the control group*.

 

Gene	Control	EH Group		EL Group		LH Group		LL Group
	dCT	dCT	p value	dCT	p value	dCT	p value	dCT	p value
TLR2	2.608	1.278	0.00012	2.561	0.9	2.244	0.32	2.234	0.31
TLR4	2.909	1.679	0.0011	2.345	0.13	2.334	0.12	2.247	0.076
TLR8	2.797	1.689	0.00012	2.391	0.17	2.129	0.029	2.402	0.19
TOLLIP	2.233	2.452	0.54	3.153	0.012	2.657	0.25	3.049	0.027
IFNGR1	2.58	1.364	0.00048	2.21	0.28	2.023	0.11	2.329	0.47
IFNGR2	2.171	1.447	0.018	2.2	0.92	1.83	0.24	2.284	0.7
MAPK14	2.548	1.641	0.0011	2.333	0.42	2.086	0.089	2.323	0.41
MIF	1.896	2.661	0.012	2.187	0.32	2.402	0.09	2.174	0.35
IKBKB	2.182	3.513	0.0011	2.767	0.14	2.509	0.41	2.464	0.48

*The CT values from qRT-PCR experiment were normalized against multiple house-keeping genes to obtain dCT values.  Each RA group was compared with the control group.  P values less than 0.05 are shown in italics.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-expression-of-genes-in-the-toll-like-receptor-and-interferon-pathways-are-associated-with-radiographic-damage-in-african-americans-with-acpa-positive-ra/